The Pediatric AIDS Working Group of the Infectious Disease section has several areas of investigation involving the treatment of HIV infection and its infectious and malignant complications. A major focus is to conduct clinical trials of novel antiretroviral therapies alone and in combination, which are initiated in pediatric patients as soon as preliminary safety and efficacy data have been established in adults. Drugs are studied over a full range of doses to assess for alterations in pharmacokinetics, identification of short and long term toxicities and interactions, and impact on immunologic function. During the last year we have initiated Phase I/II studies of two protease inhibitors, Abbott Ritonavir and Merck Indinavir, to determine the saftey and tolerance of these agents alone and in combination with reverse transcriptase inhibitors. A maximum tolerated dose (MTD) has yet to be identified with either agent, and expanded studies are planned to further assess for toxicity of these agents in children. Data generated from earlier clinical studies of 3TC (lamivudine) conducted by our group, resulted in FDA approval of this agent for use in children in November 1995. We have also recently begun clinical studies of the following novel immunomodulatory agents: recombinant IL-2, levamisole and HIV-1 immunogen vaccine. These agents are administered alone or in combination with antiretroviral therapy to children with a broad range of CD4 counts, reflecting minimal to severe immunologic dysfunction. In addition to delineation of toxicitiy and antiviral activities, an intensive focus is directed toward assessment of quantitative and qualitative measures of immune function associated with these therapies. Additional agents currently being studied include cyclodextrin itraconazole in the treatment of oropharyngeal candidiasis and BV-araU (soruvudine) for chronic recurrent zoster. A study of cidofovir in children with CMV retinal disease will open in the fall in collaboration with investigators in the National Eye Institute. We are also conducting ongoing studies of interferon-alpha and all-trans-retinoic acid in the treatment of HIV-associated lymphoproliferative disorders, in addtion to a dose-intensive chemotherapeutic regimen for treatment of non-Hodgkin's lymphoma (NHL) in HIV-infected patients. The basic laboratory research effort within our group focuses on molecular characterization of virus expression in peripheral blood and tissues, the examination of specific viral and immunogical factors associated with disease progression, and molecular studies of cellular gene expression and regulation during HIV infection. Longitudinal studies of neurocognitive function, brain imaging and immune measures in children receiving antiretroviral therapy are being conducted in addition to investigation of the pathophysiology of HIV encephalopathy. Psychosocial studies include investigation of correlates of psychosocial functioning and coping strategies in long term survivors and longitudinal examination of psychological disturbances in HIV-infected, school-aged children. Significant progress has been made in each of these areas, further advancing knowledge about the treatment of HIV disease in children and adolescents. HIV/AIDS-related work accounted for 100% of this project.